From Oncological Paradigms to Non-Communicable Disease Pandemic. The Need of Recovery Human Biology Evolution

The paradigm of the Somatic Mutation Theory (SMT) is failing, and a new paradigm is underway but not yet established. What is being challenged is a conceptual approach that involves the entire human biology and the development of chronic diseases. The behavior of breast and other solid cancers is compatible with the concept that the primary tumor is able to control its microscopic metastases, in the same way that an organ (e.g., the liver) is able to control its physiological size. This finding suggested that cancer and its metastases may behave as an organoid. The new paradigm under construction considers the origin of tumors as a disturbance in the communication network between tissue cell populations and between cells and extracellular matrix, and supports a systemic approach to the study of both healthy and pathologic tissues. The commentary provides a rationale for the role of physical exercise in the control of tumor dormancy according to a human evolutionary perspective.

Late Recurrence in Breast Cancer: To Run after the Oxen or to Try to Close the Barn?

The problem of late recurrence in breast cancer has recently gained attention and was also addressed in an international workshop held in Toronto (ON, Canada), in which several aspects of the question were examined. This Commentary offers a few considerations, which may be useful for the ongoing investigations. A few premises are discussed: (a) clinical recurrences, especially the late ones, imply periods of tumor dormancy; (b) a structured pattern of distant metastases appearance is detectable in both early and late follow-up times; (c) the current general paradigm underlying neoplastic treatments, i.e., that killing all cancer cells is the only way to control the disease, which is strictly sprouting from the somatic mutation theory, should be re-considered. Finally, a few research approaches are suggested.

The mitochondrial basis of aging and related diseases

Aging is a programmed and spontaneous life course that organisms must undergo, and as an irreversible and relatively conservative process, several theories have tried to explain its causes. Among them, the somatic mutation theory, the free radical theory, the natural cross-linking of biomolecules, the immune theory, the telomere theory, the biological clock theory, and the toxic theory are among the most widely accepted hypotheses. However, no single doctrine can fully explain the aging process. Aging is mainly manifested in the structural and functional aging and decline of organisms, and as organisms continue to age, most organs will experience varying degrees of aging and irreversible damage, although it is directly related to many diseases, aging itself is generally not considered as a disease. Any organism ages slowly over time, with the most easily observable manifestations in external changes such as diminished hair color and sagging skin. Numerous studies have shown that mitochondria are instrumental in mitigating aging as the primary provider of cellular energy, providing energy for cell growth and development as well as being the center of cellular metabolism; therefore, once mitochondria become faulty, a large number of cells will lose function, age, and thus die. In this paper, we will discuss in detail the relationship between mitochondria and aging and how external interventions can promote the function of mitochondria in delaying aging.

Environmental Carcinogenesis and Transgenerational Transmission of Carcinogenic Risk: From Genetics to Epigenetics

The dominant pathogenic model, somatic mutation theory (SMT), considers carcinogenesis as a ‘genetic accident’ due to the accumulation of ‘stochastic’ DNA mutations. This model was proposed and accepted by the scientific community when cancer mainly affected the elderly, but it does not explain the epidemiological observation of the continuous increase in cancer incidence among children and young adults. Somatic mutation theory has been proposed for a revision based on the emerging experimental evidence, as it does not fully address some issues that have proven to be crucial for carcinogenesis, namely: the inflammatory context of cancer; the key role played by the stroma, microenvironment, endothelial cells, activated macrophages, and surrounding tissues; and the distorted developmental course followed by the neoplastic tissue. Furthermore, SMT is often not able to consider either the existence of specific mutations resulting in a well-defined cancer type, or a clear relationship between mutations and tumor progression. Moreover, it does not explain the mechanism of action of the non-mutagenic and environmental carcinogens. In the last decade, cancer research has highlighted the prominent role of an altered regulation of gene expression, suggesting that cancer should be considered as a result of a polyclonal epigenetic disruption of stem/progenitor cells, mediated by tumour-inducing genes. The maternal and fetal exposure to a wide range of chemicals and environmental contaminants is raising the attention of the scientific community. Indeed, the most powerful procarcinogenic mechanisms of endocrine disruptors and other pollutants is linked to their potential to interfere epigenetically with the embryo-fetal programming of tissues and organs, altering the regulation of the genes involved in the cell cycle, cell proliferation, apoptosis, and other key signaling pathways. The embryo-fetal exposure to environmental, stressful, and proinflammatory triggers (first hit), seems to act as a ‘disease primer’, making fetal cells and tissues more susceptible to the subsequent environmental exposures (second hit), triggering the carcinogenic pathways. Furthermore, even at the molecular level, in carcinogenesis, ‘epigenetics precedes genetics’ as global DNA hypomethylation, and the hypermethylation of tumor suppressor genes are common both in cancerous and in precancerous cells, and generally precede mutations. These epigenetic models may better explain the increase of cancer and chronic/degenerative diseases in the last decades and could be useful to adopt appropriate primary prevention measures, essentially based on the reduction of maternal-fetal and child exposure to several procarcinogenic agents and factors dispersed in the environment and in the food-chains, as recently suggested by the World Health Organization.

Somatic Mutation Theory/Tissue Organization Field Theory: Has the Premise been Wrong All along?

ABSTRACT How to cite this article Sarode SC, Anand R, Sarode GS, Patil S. Somatic Mutation Theory/Tissue Organization Field Theory: Has the Premise been Wrong All along? World J Dent 2016;7(4):167-168.

Somatic Mutation Theory - Why it's Wrong for Most Cancers

Hysteron proteron reverses both temporal and logical order and this syllogism occurs in carcinogenesis and the somatic mutation theory (SMT): the first (somatic mutation) occurs only after the second (onset of cancer) and, therefore, observed somatic mutations in most cancers appear well after the early cues of carcinogenesis are in place. It is no accident that mutations are increasingly being questioned as the causal event in the origin of the vast majority of cancers as clinical data show little support for this theory when compared against the metrics of patient outcomes. Ever since the discovery of the double helical structure of DNA, virtually all chronic diseases came to be viewed as causally linked to one degree or another to mutations, even though we now know that genes are not simply blueprints, but rather an assemblage of alphabets that can, under non-genetic influences, be used to assemble a business letter or a work of Shakespearean literature. A minority of all cancers is indeed caused by mutations but the SMT has been applied to all cancers, and even to chemical carcinogenesis, in the absence of hard evidence of causality. Herein, we review the 100 year story of SMT and aspects that show why genes are not just blueprints, how radiation and mutation are associated in a more nuanced view, the proposed risk of cancer and bad luck, and the in vitro and in vivo evidence for a new cancer paradigm. This paradigm is scientifically applicable for the majority of non-heritable cancers and consists of a six-step sequence for the origin of cancer. This new cancer paradigm proclaims that somatic mutations are epiphenomena or later events occurring after carcinogenesis is already underway. This serves not just as a plausible alternative to SMT and explains the origin of the majority of cancers, but also provides opportunities for early interventions and prevention of the onset of cancer as a disease.

Real world in cancer? Epistemology of the origin of cancer: new paradigm for the majority of cancers

Background: The somatic mutation theory as the origin of cancer (carcinogenesis) was born some 100 years ago, when Theodor Boveri 1914 suggested that a combination of chromosomal defects may result in cancer. This was followed by Karl-Heinrich Bauer in 1928 suggesting that mutations could cause cancer. Subsequently, in 1953 Carl Nordling proposed that a number of mutated genes could cause cancer. Alfred Knudson in 1971 proposed that one hit (one mutation) would result in a clone of cancerous cells. This was modified to a 2-hit-theory later and it seems that cancer biology has continued to try to bolster the somatic mutation theory by recently suggesting that ‘driver’ and ‘passenger’ mutations were necessary and when this proved insufficient, others proposed the hyper-mutation theory in 2014. In the attempt to clothe the Emperor, it was forgotten that mutations found in advanced cancers are either late events or epiphenomena that occur after carcinogenesis (cancer development) and especially after the appearance of a pre-cancerous niche. Reality: Fewer than 10% of cancers are proven to be hereditary (i.e., causally related to germline mutations) and this ratio is even lower in cancers of the stomach (<1%), the colorectum (3-8%) and breast (8%). Infection-triggered cancers constitute some 15% of all cancers and the remaining about some 80% cancers are sporadic, meaning their cause is unknown. New cancer paradigm: Findings from the plant and animal kingdoms, molecular and clinical data over the last 250 years were critically reviewed and gave rise to a new cancer hypothesis containing a multi-step process of 6 sequences. These include, (1) a pathogenic biological or chemical stimulus is followed by (2) chronic inflammation, from which develops (3) fibrosis with associated changes in the cellular microenvironment. These remodeling changes result in a (4) pre-cancerous niche, which triggers the deployment of (5) a chronic stress escape strategy, and when this fails to resolve, (6) a transition of a normal cell to a cancer cell occurs. Consequences: This recently proposed cancer model explains the origins of the vast majority of cancers which are until now were referred to as ‘sporadic’ cancers. Furthermore, this theory points out the need to establish preventive measures long before a cancer becomes clinically apparent. The epistemology of the origin of cancer is reviewed and presented.

Real world in cancer? Epistemology of the origin of cancer: new paradigm for the majority of cancers

Background: The somatic mutation theory as the origin of cancer (carcinogenesis) was born some 100 years ago, when Theodor Boveri 1914 suggested that a combination of chromosomal defects may result in cancer. This was followed by Karl-Heinrich Bauer in 1928 suggesting that mutations could cause cancer. Subsequently, in 1953 Carl Nordling proposed that a number of mutated genes could cause cancer. Alfred Knudson in 1971 proposed that one hit (one mutation) would result in a clone of cancerous cells. This was modified to a 2-hit-theory later and it seems that cancer biology has continued to try to bolster the somatic mutation theory by recently suggesting that ‘driver’ and ‘passenger’ mutations were necessary and when this proved insufficient, others proposed the hyper-mutation theory in 2014. In the attempt to clothe the Emperor, it was forgotten that mutations found in advanced cancers are either late events or epiphenomena that occur after carcinogenesis (cancer development) and especially after the appearance of a pre-cancerous niche. Reality: Fewer than 10% of cancers are proven to be hereditary (i.e., causally related to germline mutations) and this ratio is even lower in cancers of the stomach (<1%), the colorectum (3-8%) and breast (8%). Infection-triggered cancers constitute some 15% of all cancers and the remaining about some 80% cancers are sporadic, meaning their cause is unknown. New cancer paradigm: Findings from the plant and animal kingdoms, molecular and clinical data over the last 250 years were critically reviewed and gave rise to a new cancer hypothesis containing a multi-step process of 6 sequences. These include, (1) a pathogenic biological or chemical stimulus is followed by (2) chronic inflammation, from which develops (3) fibrosis with associated changes in the cellular microenvironment. These remodeling changes result in a (4) pre-cancerous niche, which triggers the deployment of (5) a chronic stress escape strategy, and when this fails to resolve, (6) a transition of a normal cell to a cancer cell occurs. Consequences: This recently proposed cancer model explains the origins of the vast majority of cancers which are until now were referred to as ‘sporadic’ cancers. Furthermore, this theory points out the need to establish preventive measures long before a cancer becomes clinically apparent. The epistemology of the origin of cancer is reviewed and presented.

Tumor and the Microenvironment: A Chance to Reframe the Paradigm of Carcinogenesis?

The somatic mutation theory of carcinogenesis has eventually accumulated an impressive body of shortfalls and paradoxes, as admittedly claimed by its own supporters given that the cell-based approach can hardly explain the emergence of tissue-based processes, like cancer. However, experimental data and alternatives theories developed during the last decades may actually provide a new framework on which cancer research should be reframed. Such issue may be fulfilled embracing new theoretical perspectives, taking the cells-microenvironment interplay as the privileged level of observation and assuming radically different premises as well as new methodological frameworks. Within that perspective, the tumor microenvironment cannot be merely considered akin to new “factor” to be added to an already long list of “signaling factors”; microenvironment represents the physical-biochemical support of the morphogenetic field which drives epithelial cells towards differentiation and phenotype transformation, according to rules understandable only by means of a systems biology approach. That endeavour entails three fundamental aspects: general biological premises, the level of observation (i.e., the systems to which we are looking for), and the principles of biological organization that would help in integrating and understanding experimental data.